VIENNA, AustriaSince most palliative care pain patients
will require one or more changes in drugs due to inadequate pain
relief, physicians caring for terminally ill patients must be
familiar with multiple drugs and routes of delivery, Eduardo
Bruera, MD, chairman of the Pain Department, M.D. Anderson Cancer
Center, said at the 9th World Congress on Pain, sponsored by the
International Association for the Study of Pain.
Dr. Bruera, who chaired a session on cancer pain and palliative care,
discussed in particular the use of oxycodone and methadone in this
setting. These two older opioid agents are being increasingly used in
cancer pain, and Dr. Bruera pointed out why physicians may need to
take extra care when converting patients to or from these opioids.
Oxycodone has been used as both short-acting and sustained-release
oral preparations as well as a parenteral preparation for management
of cancer pain, Dr. Bruera said. Oxycodone was found to have about
50% greater potency compared to morphine, according to studies by
Heiskennan, so that a 30 mg dose of oral morphine sulfate would be
equivalent to approximately 20 mg of oral oxycodone. Dr. Bruera
noted, however, that the conversion ratio reported in other studies
ranges from 1:1 to 1:2.
In a double-blind, randomized, crossover trial comparing
sustained-release morphine sulfate every 12 hours with sustained-release
oxycodone every 12 hours at a 3:2 ratio, Dr. Bruera found similar
pain control, sedation, and other side effects with the two agents.
Fewer rescue medications were needed at night with use of both
sustained-release agents, compared with use of short-acting agents.
Oxycodone, however, must be biologically converted by the hepatic
enzyme cytochrome P450 2D6 into its active metabolite, oxymorphone,
to provide analgesia. Approximately 10% to 15% of the population have
genetically low concentrations of this enzyme, which can also be
inhibited by such drugs as fluoxetine (Prozac) or quinidine.
James Clearly, MD, demonstrated that animals with low levels of this
enzyme required a 10-fold increase in oxycodone dose in order to have
the same effects.
Whether this effect occurs in humans has not yet been determined.
However, Dr. Bruera presented the case of a patient who had
inadequate pain relief with oxycodone for cancer-related pain due to
bone metastases. Over 10 days, the oxycodone dose was escalated
without significant improvement in pain.
When switched to an equianalgesic dose of hydromorphone, the patient
developed symptoms of opioid toxicity requiring reversal with
naloxone. This implied that the patient needed a lower dose of
hydromorphone, a drug that, unlike oxycodone, does not require
bioconversion to have analgesic properties.
Methadone, a relatively inexpensive opioid for chronic pain, does not
have active metabolites. It is well absorbed by the oral route and
exhibits both µ-opioid and NMDA (N-methyl D-aspartate) receptor
antagonism effects. However, it has a relatively long half-life with
significant interindividual variability, which can result in
accumulation and toxicity.
Dr. Bruera found that patients could be changed from morphine sulfate
or hydromorphone to methadone with acceptable analgesia and side
effects. However, methadone was significantly more potent than
previously expected, and the potency and conversion ratios were even
greater for patients changed from higher doses of other opioids to
For instance, for oral morphine doses from 30 to 90 mg/day, studies
showed that the dose conversion ratio was 4:1. For morphine doses
from 90 to 300 mg/day, the ratio when switching to methadone was 8:1,
and for oral morphine doses higher than 300 mg/day, the ratio for
conversion to methadone was 12:1. However, there tends be a
significant amount of interindividual variability. This implies that
there is little cross tolerance between methadone and other opioids,